Neurofibromatosis: causes, symptoms, diagnosis, treatment

Neurofibromatosis (Recklinghausen's disease) is a hereditary disease characterized by a malformation of ecto- and mesodermal structures, mainly skin, nervous and bone systems, with an increased risk of developing malignant tumors.

Neurofibromatosis is a relatively frequent, highly retentive, inherited autosomal dominant with variable expressiveness, a disease that belongs to the group of phakomatoses. A high frequency (almost half of the cases) of new mutations is proved. According to the classification of VM Riccardi (I982), seven types of disease are distinguished. The most common (85% of all cases) is type I (syn: classical neurofibromatosis, peripheral neurofibromatosis, Recklinghausen's disease), the gene locus is 17q 11.2. Genetic independence of type II (central neurofibromatosis, bilateral neurinoma of the auditory nerves), and the locus of the gene - 22qll-13.1, is proved.

[1], [2], [3], [4]

Causes and pathogenesis of neurofibromatosis

Recklinghausen's disease is an autosomal dominant disease, the gene locus is 17q 11.2. The disease is caused by spontaneous mutation of the gene. The absence of neurofibromatosis as a result of gene mutation can contribute to the onset of the tumor process. Most of the cases are the result of new mutations that are mostly of paternal origin.

[5], [6], [7]

Pathomorphology of neurofibromatosis

Neurofibromas are located in the dermis and upper part of the subcutaneous tissue, do not have a capsule, consist of spindle-shaped and rounded cells. Most tumors have many tissue basophils. The stroma forms a significant part of the tumor. It is represented by loosely arranged collagen fibers, the bundles of which are intertwined, go in different directions, are pale with eosin, and also with thin-walled vessels. Perivascularly located tissue basophils and macrophages. Immunomorphological studies have shown that the stroma is dominated by collagen types I and III. The presence of a large amount of type III collagen testifies to the immaturity of the tumor. A positive reaction to the protein S-100, a marker of neurogenic cells, indicates the neurogenic origin of the tumor. Sometimes mucoid dystrophy of the stroma is noted in some areas or in the entire tumor, revealed in the form of metachromasia when stained with toluidine blue. Histological variants of neurofibroma are described: myxoid. Containing a lot of mucin in the stroma; plexiform, consisting of numerous neural bundles of irregular configuration. Enclosed in a matrix containing various amounts of spindle-shaped cells, corrugated wavy fibers, mucins and tissue basophils; a structure that resembles tactile bodies; pigmented (or melanocytic); reminding bulging dermatofibrosarcoma.

With electron microscopic examination, it was found that rounded cells are similar in structure to neurolematocytes, the fine structure of spindle-shaped cells corresponds to that of perineural fibroblasts. In the cytoplasm of neurolemocytes, axons are present, a continuous basal membrane 50-70 nm in width surrounds the cells. Perineural fibroblasts have an elongated shape, thin bipolar processes, in the course of the cell membrane there are pinocytotic vesicles surrounded by a discontinuous, sometimes multilayered basal membrane. The basal membrane surrounding the cells contains collagen IV and V types and laminin. Both types of cells that make up the tumor are able to synthesize procollagen. Some authors note in neurofibromas the predominance of certain cell elements. Tumors consisting exclusively of neurolematocytes or only from cells of the perineural fibroblast type are described.

When histological examination of the skin from the spot area, the colors "coffee with milk" in the basal and supra-basal prickly epithelial cells reveal a large amount of melanin. Pigmentary granules are located both in melanocytes and in epithelial cells. Giant granules (macromelanosomes) having a spherical or ellipsoidal shape are characteristic for neurofibromatosis, located not only in the basal layer, but also higher up to the stratum corneum. An electron microscopic study of these elements showed that melanocytes differ little in structure from those of normal cells. There are three types of melanosomes in them: small melanosomes of the usual structure (they predominate); larger granular medium-density electron density with densified center and macromelanosomes - giant pigment granules. Macromelanosomes are usually located near the nucleus, they consist of an electron-dense matrix, electronically dense membranous round bodies with a diameter of 40-50 nm with less dense granules inside and fine granules of average electron density. The number and distribution of these components are distinguished by three types of macromelanosomes, which, apparently, substitute themselves for different stages of their development.

In the region of pseudoatrophic spots, a decrease in the number of collagen fibers in the dermis and perivascular clusters of cells, which are neurolemocyte-type cells surrounding numerous myelin and demyelinic nerve fibers, are found.

Histological examination of pigment spots on the palms revealed limited acanthosis with lengthening of the epidermal outgrowths, an increase in the melanin content in the epidermis without increasing the amount of melanocytes. In the underlying dermis, small accumulations of spindle-shaped cells and corrugated collagen fibers resemble miniature neurofibromas.

Schwannomas (neirolemmoma) are encapsulated tumors consisting of elongated spindle-shaped cells (Schwann cells) and fibrillar eosinophilic intercellular matrix.

Plots of accumulation of parallel rows of cells are called the Anthony A. The parallel rows of cells, separated from each other by a cell-free space, form the characteristic bodies of Verokey. The areas of the edematous mucinous stroma are called the zone of Anthony V.

Histogenesis of neurofibromatosis

Many issues of histogenesis are controversial, the causes of the clinical polymorphism of the disease are unclear. The concept of neurocristopathy, proposed by RP Bolande (I974), makes it possible to explain the polymorphism of clinical manifestations by disturbing the development of the neural crest, migration, growth and differentiation of its cells. Cells originating from the neural crest are localized in various organs and systems, and disturbances in their function in one organ can lead to simultaneous disturbance in other tissues.

Immunohistochemical studies have shown that neurofibroma cells have a neurogenic origin. Perineural fibroblasts can differentiate from mesodermal elements or from a primitive neuroectodermal mesenchyme. With tissue culture, it has been shown that the proliferation of perineural fibroblasts occurs under the influence of a fibroblast-stimulating factor, but the lack of its stimulating effect on the culture of fibroblasts in healthy individuals indicates that tumor fibroblasts differ significantly from normal fibroblasts. N. Nakagawa et al. (1984) suggest that macromelanosomes are formed during the decay of complexes of ordinary melanosomes that merge with each other and with lysosomes, forming autophagosomes. In support of this point of view, data on the presence of acidic phosphatase characteristic of lysosomes in macromelanosomes, as well as the detection of macromelanosomes in other cells (epithelial cells, intra-epidermal macrophages) are given.

Histopathology of neurofibromatosis

In neurofibromas proliferation of spindle-shaped cells with cores of corrugated outlines, fibrous fibers, thin-walled vessels, remnants of nerve bundles, tissue basophils, pigment spots - giant pigment granules (macromelanosomes) and DOPA-positive melanocytes are determined. In the stage of active growth of neurofibrom there is an increase in the number of acidic mucopolysaccharides.

Symptoms of neurofibromatosis

The disease mainly begins in childhood. The clinical picture is characterized by the appearance of pigment spots and neurofibroma. The earliest sign are multiple, oval, small pigmented spots with a smooth surface of a yellowish brown color (the color of "coffee with milk"). Spots are located mainly on the trunk, in the armpits and inguinal folds. With age, the size and number of spots increase. The second characteristic symptom are neurofibromas (cutaneous and / or subcutaneous) in the form of painless hernial protrusions up to a few centimeters in diameter. When palpation of tumorous formations, the finger falls like a void (a symptom of "falling into the void," or the phenomenon of "button from the bell"). They have the color of normal skin, pinkish-bluish or brownish, soft consistency or, rarely, dense. Neurofibromas are located mainly on the body but can be found in any areas. Occasionally diffuse neurofibromatosis with excessive overgrowth of connective tissue of the skin and subcutaneous tissue with the formation of giant tumors (giant neurofibromas). Plexiform neurofibromas often appear along the nerve trunks (cranial nerves, nerves of the neck and extremities). They are most often transformed into neurofibrosarcomas (malignant schwannomas). In the neurofibre zone there may be disturbances of various types of sensitivity. Subjectively, pain, paresthesia, itching are felt. At present, the presence of two or more of the following symptoms should be taken into account for the formulation of a lyagnosis:

• six or more spots of color "coffee with milk" more than 5 mm in diameter in the pre-pubertal and more than 15 mm in post-pubertal age;
• two or more neurofibromas of any type or one plexiform neurofibroma;
• small pigmentation spots, reminiscent of freckles, in the axillary and inguinal folds;
• glioma of the optic nerve;
• two or more litters;
• dysplasia of the wing of the sphenoid bone of the skull or thinning of the cortical layer of tubular bones with or without pseudoarthrosis;
• neurofibromatosis in relatives of the first degree of kinship.

Multiple tumor-like formations can be noted in the oral cavity, in the region of the spinal roots, inside the skull, which is manifested by the corresponding symptomatology. The disease is often combined with pathologies of the musculoskeletal system, nervous, endocrine and cardiovascular systems.

The main skin symptoms of Type I neurofibromatosis are pigmented spots and neurofibromas. The earliest symptom is congenital or appearing soon after birth large pigment spots of a yellowish brown color ("coffee with milk"). Small pigmented spots, reminiscent of freckles, are located mainly in the armpits and inguinal folds. Neurofibromas (skin and / or subcutaneous), usually multiple, usually appear in the second decade of life. They have the color of normal skin, pinkish-bluish or brownish. Above deeply located tumors is characterized by the presence of a hernial protrusion, on palpation of which the finger falls like into a void. Plexiform neurofibromas, which are diffuse tumor-like proliferation along the nerve trunks, are usually congenital. They can be located as superficially - along the cranial nerves, nerves of the neck and extremities, and deep in the mediastinum, retroperitoneal space, paraspinally. Superficial plexiform neurofibromas can have the appearance of saccularly hanging, massive lobular tumors, often hyperpigmented. In the depths of their palpated thickened sinuous nerve trunks (elefanthiasis neurofibromatosa). For the presence of deep plexiform neurofibroma can indicate large, hair-covered pigment spots, especially intersecting the midline of the body. Plexiform neurofibromas are most often malignant with the development of neurofibrosarcoma. Of other skin manifestations, sometimes bluish-bluish and pseudoatrophic spots, melanotic patches on the palms and soles, neurinomas are sometimes observed. In children, the appearance of juvenile xanthogranules often accompanies the development of myelocytic leukemia.

Pathological changes can be observed in almost all organs and systems, most often in the organs of vision, nervous, bone and endocrine systems.

For the diagnosis of type I neurofibromatosis, two or more of the following signs are necessary (WHO, 1992): six or more "coffee with milk" spots more than 5 mm in diameter in pre-pubertal and / or 15 mm at post-pubertal age; two or more neurofibromas of any type or one plexiform neurofibroma; the presence of small pigmentation spots, reminiscent of freckles, in the axillary and inguinal folds; glioma of the optic nerve; two or more Lisha nodes; dysplasia of the wing of the sphenoid bone of the skull or thinning of the cortical layer of tubular bones with or without pseudoarthrosis; presence of the same criteria type I neurofibromatosis in relatives of the first degree of kinship.

Based on the correlation of the main skin manifestations, we isolated 4 clinical forms of type I neurofibromatosis: with the presence of predominantly neurofibroma; large pigmented spots; generalized finely-spotted; mixed.

The development of type II neurofibromatosis (central) is associated with the absence of the primary product of the schannoma (merlin) gene, which presumably inhibits tumor growth at the level of cell membranes. Skin manifestations can be minimal: pigment spots occur in about 42% of patients, neurofibromas - in 19%. More painful, dense and mobile subcutaneous tumors - neurinomas (schwannomas) are more characteristic. Two-sided neurinoma (shvannoma) of the auditory nerve develops in almost all cases and causes hearing loss, usually at the age of 20-30 years. Diagnosis of type II neurofibromatosis can be made if one of the following criteria is present: an x-ray-confirmed bilateral neurinoma of the auditory nerve; bilateral neurinoma of the auditory nerve from a relative of the first degree of kinship and the presence of a proband of any of the signs:

• unilateral neurinoma of the auditory nerve;
• plexiform neurofibromas or two other tumors: meningiomas, gliomas, neurofibromas regardless of their location;
• any intracranial or cerebrospinal tumor.

III, or mixed (central-peripheral) type of neurofibromatosis is characterized by tumors of the central nervous system, developing at the age of 20-30 years and, as a rule, rapidly progressing. The presence of neurofibre in the palm region is considered as a diagnostic criterion that allows to differentiate the disease from the second central type, however, according to our data, neurofibromas on the palms and soles are found in 24% of patients with type 1 neurofibromatosis.

IV type (variant) of neurofibromatosis differs from the central one by more numerous dermal neurofibromas, a greater risk of developing gliomas of the optic nerve, a neurolemm, and meningiomas.

V type of neurofibromatosis - segmental neurofibromatosis, characterized by unilateral lesion (neurofibromas and / or pigment spots) of any cutaneous segment or part thereof. The clinical picture may resemble hemihypertrophy.

VI type of neurofibromatosis is characterized by the absence of a neurofibre,
only pigment spots are detected.

VII type of neurofibromatosis - a variant with a late onset of the disease, characterized by the appearance of a neurofibre after 20 years of age. 

The intestinal form of neurofibromatosis is manifested by the development of intestinal tumors in adults, the symptoms characteristic of the classical type I are rarely observed.

Pigmented spots can be an integral part of Leschke syndrome. Neurofibromatosis can be combined with Noonan syndrome, pheochromocytoma and duodenal carcinoid.

Treatment of neurofibromatosis

Large neurofibromas can be surgically removed.